The Efficacy of Targeted Therapy in Veterinary Medicine http://media.wix.com/ugd/58b0bb_d2cd03ab06bb33a03d36f28e088e3c50.pdf

WARNING LETTER

Dear Mr. Moussy:

The U.S. Food and Drug Administration (FDA), Center for Veterinary Medicine (CVM), Division of Surveillance has reviewed your promotional materials for Kinavet-CA1® (masitinib mesylate), which are available on the website for Kinavet-CA1®, www.kinavet.com. These materials include the Kinavet-CA1® website, the material entitled “Masitinib – Targeted Therapy in Veterinary Medicine,” (http://media.wix.com/ugd/58b0bb_59ae22d022dc18ab7aee3a6eb8a4832e.pdf), and the material entitled “The Efficacy of Targeted Therapy in Veterinary Medicine” (http://media.wix.com/ugd/58b0bb_d2cd03ab06bb33a03d36f28e088e3c50.pdf), which wassubmitted to CVM in a Drug Experience Report(DER) dated June 8, 2011.

These promotional materials provide evidence that Kinavet-CA1® is intended for new uses for which it lacks approval, conditional approval or an index listing, and for which its labeling does not provide adequate directions for use. This causes Kinavet-CA1® to be unsafe and adulterated and renders Kinavet-CA1® misbranded. See 21 U.S.C. §§ 360b, 351(a)(5), 352(f), 331(a). In addition, these materials are false and misleading because they omit information regarding the effectiveness of Kinavet-CA1® and minimize the risks associated with the product. Therefore, these materials misbrand Kinavet-CA1® within the meaning of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and make its distribution violative of the FD&C Act.21 U.S.C. § 352(a) and (n).

Unapproved New Animal Drug Claims

Kinavet-CA1® is conditionally approved for the following indications: treatment of nonresectable Grade II or III cutaneous mast cell tumors in dogs that have not previously received radiotherapy and/or chemotherapy, except corticosteroids. As described below, the materials cited in this letter repeatedly suggest that Kinavet-CA1® iseffective for a broader range of indications than are described in the approved labeling.

1.Kinavet-CA1® Website

The section of the Kinavet-CA1® website entitled “Benefits of Kinavet®”(http://www.kinavet.com/#!benefits-of-kinavet/c414) contains the following statement: “The molecular targets of Kinavet-CA1® make it potentially well-suited for treating non-oncology diseases, such as canine atopic dermatitis or feline asthma;…”

In addition, the section of the website entitled “Development Program for Feline Treatments” (http://www.kinavet.com/#!feline-treatments/c14hd) presents information that suggests Kinavet-CA1® can be used to treat feline-related oncological and inflammatory diseases. For example, the webpage states the following: “Off-label use of Kinavet-CA1 has again revealed some interesting case studies. These include encouraging results in asthmatic cats.”; “Oncology-related cases in cats have also been reported. One feline subject presenting with mast cell tumor experienced rapid improvement in clinical status after 7 days of masitinib treatment…”; “Another subject had a metastasized cutaneous melanoma for which the primary tumor had been resected. After 6 months of daily Kinavet-CA1 treatment the metastasis had totally disappeared and lymph nodes were stable without need for further resection.”

2.“Masitinib Scientific Data for Veterinary Medicine”

Page 2 of the document entitled “Masitinib Scientific Data for Veterinary Medicine” (http://media.wix.com/ugd/58b0bb_59ae22d022dc18ab7aee3a6eb8a4832e.pdf) contains the statement: “Everyone knows that a picture is worth 1000 words, and this saying has never been truer than when comparing before and after images from successful treatment of tumors or inflammatory conditions…” The images in this detailer include case studies of masitinib treatment of canine atopic dermatitis. For example, on page 9 is a section titled “Case Studies of masitinib treatment of canine atopic dermatitis.” The detailer also contains a bolded heading that states “…a wide range of other cancers and immune-mediated disorders are currently being investigated.” Below this statement is a table that summarizes the“Development program of masitinib in veterinary medicine.” (Page 8) Target diseases suggested in this material include T-cell lymphoma, melanoma, splenic hemangiosarcoma, tumors treated with chemotherapies, atopic dermatitis, arthritis, asthma and inflammatory bowel disease.

3.“The Efficacy of Targeted Therapy in Veterinary Medicine”

A link to this detailer is provided on the “How to Order Kinavet-CA1®” page of the Kinavet-CA1® website. The link is contained within this statement: “Please look through the package insert and brochure. If you have any questions, do not hesitate to call the office.” This statement solicits potential customers to obtain and to read this detailer. The detailer contains the following statements:

Several other canine cancer indications are being investigated for masitinib, including lung, pancreas, colon and multiple myeloma. The beneficial action of Kinavet CA1® in oncology results from the ability of Kinavet CA1® to: (1) block the proliferation of tumoral cell lines; (2) slow down tumor progression and reduce the emergence of metastases; and (3) potentiate the effect of cytotoxic chemotherapies in various cancer cell lines, including melanoma, osteosarcoma, hemangiosarcoma, histosarcoma, for combination therapies.

Mast cells are involved in normal immune reactions, as well as pathological reactions observed in chronic inflammatory diseases, such as atopic dermatitis, asthma, irritable bowel syndrome and rheumatoid arthritis. By merit of a combined inhibition on c-Kit and Lyn, Kinavet CA1® is particularly efficient in controlling the proliferation, differentiation and degranulation of mast cells. Thus, Kinavet CA1® has further potential in the treatment of mast cell dysfunctions and related complications.”

These statements provide evidence that Kinavet-CA1® is intended for new uses for which it lacks approval, conditional approval or an index listing, making Kinavet-CA1® an unapproved new animal drug for those uses. Further, the labeling does not provide adequate directions for those uses. Unapproved uses of new animal drugs are deemed unsafe under section 512(a) of the FD&C Act [21 U.S.C. § 360b(a)] and therefore adulterate the drug under section 501(a)(5) of the FD&C Act [21 U.S.C. § 351(a)(5)] .

This evidence that Kinavet is an unapproved new animal drug is particularly compelling because Kinavet is conditionally approved under section 571 of the FD&C Act [21 U.S.C. § 360ccc] and therefore its extra-label use is not permitted. Pursuant to section 512(a)(4) of the FD&C Act [21 U.S.C. § 360b(a)(4)], only drugs approved under section 512(b) of the FD&C Act [21 U.S.C. § 360b(b)], and not those conditionally approved under section 571 of the FD&C Act [21 U.S.C. § 360ccc], may be used in an extra-label manner. Thus, extra-label use of Kinavet-CA1® is not allowed and materials providing evidence that Kinavet-CA1® is intended for such uses cause Kinavet-CA1® to be unsafe under section 512(a) of the FD&C Act [21 U.S.C. § 360b(a)] and therefore adulterated under section 501(a)(5) of the FD&C Act [21 U.S.C. § 351(a)(5)]. In addition the lack of adequate directions for use renders Kinavet-CA1® misbranded under section 502(f) of the FD&C Act [21 U.S.C. § 352(f)] . Under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)], an adulterated or misbranded animal drug may not be introduced or delivered for introduction into interstate commerce.

Omission of Material Facts

The EFFECTIVENESS section of the approved label contains the following statement:

“Reasonable Expectation of Effectiveness

Effectiveness has not been demonstrated for Kinavet-CA1®. A reasonable expectation of effectiveness for conditional approval was based on time to progression (TTP) in a subpopulation of dogs in the following study… The study was not designed for TTP to support substantial evidence of effectiveness.”

However, none of the materials cited in this letter contain a statement that the effectiveness of Kinavet-CA1® has not been established. Furthermore, the CAUTION statement of the approved label contains the following statement:

“Use only as directed. It is a violation of Federal law to use this product other than as directed in the labeling.”

The document entitled “Masitinib Scientific Data for Veterinary Medicine” does not contain this statement.

Because the promotional materials omit information related to effectiveness and cautions [see 21 CFR 202.1(e)(1)] they cause the drug to be misbranded under sections 502(a) and 502(n) of the FD&C Act [21 U.S.C. §§ 352(a) and (n)]. Under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)], an adulterated animal drug may not be introduced or delivered for introduction into interstate commerce.

Omission and Minimization of Risk Information

1.For Human Users

The approved label for Kinavet-CA1® contains a HUMAN WARNINGS section, which states the following:

“NOT FOR USE IN HUMANS. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Children should not come into contact with KINAVET-CA1. Keep children away from feces, urine, or vomit of treated dogs.

To avoid exposure to drug, wash hands with soap and water after administering Kinavet-CA1® and wear protective gloves to prevent contact with feces, urine, vomit, and broken or crushed Kinavet-CA1® tablets. Place all waste material in a plastic bag and seal before general disposal. If eyes are accidentally exposed to the drug, rinse eyes with water immediately. In case of accidental ingestion by a person, seek medical advice immediately, show the package insert or label to the physician.

Pregnant women, women who may become pregnant, or nursing mothers should pay special attention to these handling precautions (see handling instructions above). KINAVET-CA1 may harm an unborn baby (cause birth defects). For pregnant and nursing women, accidental ingestion of KINAVET-CA1 may have adverse effects on pregnancy or the nursing baby.”

However, the website and the materials discussed in this letter contain no human warning information.

2.For Treated Dogs

The complete prescribing information for Kinavet-CA1® contains the following:

In the WARNINGS section:

“Masitinib was associated with life-threatening or fatal hypoalbuminemia and anemia in field studies and the 39-week safety study. The studies provide evidence that severe adverse reactions may be prevented if dogs are monitored for hypoalbuminemia every 2 weeks and for anemia every 4 weeks, and treatment is discontinued if hypoalbuminemia, proteinuria or anemia occur (see Table 3 and ANIMAL SAFETY).”

In the CONTRAINDICATIONS section:

“Do not initiate KINAVET-CA1 tablet treatment in dogs with: Hypoalbuminemia…proteinuria…azotemia…anemia…neutropenia…or hyperbilirubinemia...Do not use in dogs that are pregnant, lactating or intended for breeding. Masitinib caused impaired fertility, fetal resorptions and abnormal development (delayed ossification) in rats.”

In the PRECAUTIONS section:

“The safe use of KINAVET-CA 1 tablets has not been evaluated in dogs younger than 2 years of age. KINAVET-CA 1 cannot be safely dosed in dogs weighing less than 7 kg (15.4 lbs).”

Despite the WARNINGS, CONTRAINDICATIONS, PRECAUTIONS, AND ADVERSE REACTIONS information cited above, the portion of the webpage entitled “Facts About Kinavet,” contains only the following statement:

“Kinavet-CA1® is a safe treatment of mast cell tumors. Kinavet-CA1® is generally well tolerated with medically manageable side-effects.”

Similarly, the detailer document, “Masitinib Scientific Data for Veterinary Medicine,” containsa brief statement regarding the risk of the drug in section 2, the sixth bullet point on p. 7, as follows:

“Masitinib is generally well tolerated with medically manageable side-effects. The most common side effects that may occur with masitinib include diarrhea and vomiting. To minimize the risk of possible adverse drug effects, and in particular protein loss syndrome, regular checkups are required.”

Thus, these materials omit important warning information and do not contain a true statement of information related to side effects, contraindications and effectiveness [see 21 CFR 202.1 (e)(1)]. By failing to include this information, they also suggest that Kinavet-CA1® is safer than has been demonstrated by substantial evidence or substantial clinical experience [see 21 CFR 202.1 (e)(6)(i)]. Therefore these materials cause the product to be misbranded under sections 502(a) and 502(n) of the FD&C Act [21 U.S.C. §§ 352(a) and (n)]. Under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)], a misbranded animal drug may not be introduced or delivered for introduction into interstate commerce.

Conclusion and Requested Action

AB Science should immediately cease misbranding Kinavet-CA1® and introducing it into interstate commerce for unapproved uses for which it lacks adequate directions. .

The violations cited in this letter do not necessarily constitute an exhaustive list. It is your responsibility to assure that your promotional materials for Kinavet-CA1® comply with all the requirements of the FD&C Act and its implementing regulations. You should take prompt action to correct the violations cited in this letter. Failure to correct the violations discussed above may result in enforcement action by FDA without further notice, including seizure and injunction.

Please submit a written response within fifteen (15) calendar days of receipt of this letter describing how you intend to comply with this request, listing any promotional materials for Kinavet-CA1® that contain statements such as those described above, and explaining your plan for discontinuing use of such materials or, in the alternative, your plan to cease distribution of Kinavet-CA1®. ] If you cannot complete corrective action within 15 calendar days, state the reason for the delay and the time within which you will complete the correction.